Overcoming Blindness As a 3-year-old, Michael May was injured by a chemical explosion that destroyed his left eye and damaged the surface of his right eye so badly that he was blind. He could tell whether it was day or night, but otherwise he couldn't see anything. An early attempt to restore his sight with corneal transplants failed, but Michael seemed undaunted. He learned to play Ping-Pong using his hearing alone (but only on the table at his parents' house, where he learned to interpret the sound cues). Michael also enjoyed riding a bicycle, but his parents made him stop after he crashed first his brother's bike and then his sister's. As an adult, Michael became a champion skier, marrying his instructor and raising two
sons. He also started his own company, making equipment to help blind people navigate on their own. Then, when Michael was 46, technical advances made it possible to restore vision in his right eye. As soon as the bandages were removed, he could see his wife's blue eyes and blond hair. But even years later, he could not recognize her face unless she spoke to him, or recognize three-dimensional objects like cubes or spheres unless they were moving. Michael could still ski, but he found that he had to close his eyes to avoid falling over. On the slopes, seeing was more distracting than helpful. The doctors could tell that images were focusing properly on Michael's retina, so why was his vision so poor?
Picture, if you can, the number of neurons in the mature human brain-- more than 80 billion (Herculano-Houzel, 2012). There are many types of neurons, each forming a vast array of hundreds or thousands of connections. More than 100 trillion synapses are formed to guide our thoughts and behavior! Yet each of us began as a single microscopic cell, the fertilized egg. How can one cell divide and grow to form one of the most complicated machines on Earth, perhaps in the universe? No one can answer that question in detail, but in this chapter we'll learn the basic processes at work in the extraordinary developing brain.
See Video 4.1: Understanding Blindness and the Brain
4.1Growth and Development of the Brain Are Orderly Processes
View Animation 4.2: Brain Explorer View Activity 4.1: Development of the Nervous System ectoderm The outer cellular layer of the developing embryo, giving rise to the skin and the nervous system. neural tube An embryonic structure with subdivisions that correspond to the future forebrain, midbrain, and hindbrain. forebrain The front division of the brain, which in the mature vertebrate contains the cerebral hemispheres, the thalamus, and the hypothalamus. midbrain The middle division of the brain. hindbrain The rear division of the brain, which in the mature vertebrate contains the cerebellum, pons, and medulla. embryo The earliest stage in a developing animal. fetus A developing individual after the embryo stage.
In the first part of the chapter, we describe brains in terms of their progress from a single fertilized egg to a machine containing billions of neurons with an incredible number of connections. Learning this material should allow you to: 4.1.1 List the six stages of cellular processes needed for brain development. 4.1.2 Describe the two phases of brain development characterized by the loss of structures. 4.1.3 Identify the basic mechanism that directs each developing neuron to take on the appropriate structure and function. 4.1.4 Discuss the significance of generating new neurons in adulthood. Within 12 hours after a human egg is fertilized, the single cell begins dividing, forming a small mass of homogeneous cells, like a cluster of grapes, that is a mere 200 micrometers in diameter. Within a week the emerging human embryo shows three distinct cell layers (FIGURE 4.1A)--the beginnings of all the tissues of the body. The nervous system develops from the outermost layer, called the ectoderm (from the Greek ektos, "out," and derma, "skin"). As the cell layers thicken, they grow to form a groove that will become the midline and then the neural groove. At the head end of this, a thickened collection of cells forms (FIGURE 4.1B). The tops of the neural groove come together to form the neural tube (FIGURE 4.1C), the beginning of the central nervous system (CNS). At the anterior part of the neural tube, three subdivisions become apparent. These subdivisions correspond to the future forebrain (cortical regions, thalamus, and hypothalamus), midbrain, and hindbrain (cerebellum, pons, and medulla) (FIGURE 4.1D and E), which were discussed in Chapter 1. The interior of the neural tube becomes the fluid-filled cerebral ventricles of the brain, the central canal of the spinal cord, and the passages that connect them. By the end of the eighth week, the human embryo shows the rudimentary beginnings of most body organs. The rapid development of the brain is reflected in the fact that by this time the head is half the total size of the embryo! The developing human is called an embryo during the first 10 weeks after fertilization and a fetus thereafter. Development of the nervous system can be divided into six distinct stages From a cellular viewpoint it is useful to consider brain development as a sequence of six distinct stages. The six stages proceed at different rates and times in different parts of the nervous system. Some of the stages may overlap even within a region: 1. Neurogenesis, the mitotic division of nonneuronal cells to produce neurons 2. Cell migration, the massive movements of nerve cells or their precursors to establish distinct nerve cell populations (nuclei in the CNS, layers of the cerebral cortex, and so on) 3. Cell differentiation, the refining of cells into distinctive types of neurons or glial cells 4. Synaptogenesis, the establishment of synaptic connections as axons and dendrites grow 5. Neuronal cell death, the selective death of many nerve cells 6. Synapse rearrangement, the loss of some synapses and the development of others, to refine synaptic connections, which extends throughout our lifespan
(A) 18 days The embryo consists of three layers of cells: endoderm, mesoderm, and ectoderm.
A thickening of the ectoderm leads to development of the neural plate.
(B) 20 days The neural groove begins to develop.
E from J. C. Larroche, 1977. Developmental pathology of the neonate. Excerpta Medica. Amsterdam, Netherlands
Development of the Brain 123 (E) In these views of the human brain (shown at one-third size) at several stages of fetal development, note the gradual emergence of gyri and sulci. 10 weeks 15 weeks
(C) 22 days The groove has closed to form the neural tube, with the beginning of the brain at the anterior end.
(D) 25 days Three major divisions of the brain--forebrain, midbrain, and hindbrain-- are discernible. Neural tube
FIGURE 4.1 Development of the Nervous System in the Human Embryo and Fetus
Watson/Breedlove HThuemMainnds'saMreacuhniniqe ue among primates in showing dramatic brain growth after birth, as iFloluunsdtartaitoends obf yBrFaiInGaUnRd BEeh4a.v2ioorn4ethe next page. MM4e_04.01 09/02/20
41 weeks View Animation 4.3: Stages of Neuronal Development
FIGURE 4.2 Fetal-like Rapid Development of the Brain outside the Womb (After B. Bogin, 1997. Yearb. Phys. Anthropol. 40: 63.)
The human brain continues growing rapidly after birth, rivaling fetal (A) rates until midchildhood.
At birth, brain weight relative to body weight is similar in humans and chimps.
Further brain development after birth is modest in chimpanzees.
See Video 4.4: Migration of a Neuron along a Radial Glial Cell
The protracted brain development after birth results in a much larger brain, relative to body size, in humans than other apes or Old World monkeys.
neurogenesis The mitotic division of nonneuronal cells to produce neurons. mitosis The process of division of somatic cells that involves duplication of DNA. v0e8n/2tr5i/c2u0lar zone Also called ependymal layer. A region lining the cerebral ventricles that displays mitosis, providing neurons early in development and glial cells throughout life. cell migration The movement of cells from site of origin to final location. gene expression The process by which a cell makes an mRNA transcript of a particular gene. cell differentiation The developmental stage in which cells acquire distinctive characteristics, such as those of neurons, as a result of expressing particular genes. synaptogenesis The establishment of synaptic connections as axons and dendrites grow.
Cell proliferation produces cells that become neurons or glia The production of neurons is called neurogenesis. Neurons themselves do not divide, but the cells that will give rise to neurons begin as a single layer of cells along the inner surface of the neural tube. These cells divide in a process called mitosis, which takes place within the ventricular zone inside the neural tube (FIGURE 4.3A). Eventually, some cells leave the ventricular zone and begin transforming into either neurons or glial cells. As the nervous system grows, cell migration follows, as the cells move over relatively long distances to fill out the brain (FIGURE 4.3B). Newly arrived cells in the brain bear no more resemblance to mature nerve cells than they do to the cells of other organs. Once the cells reach their destinations, however, gene expression begins, that is, the cells begin to use, or express, particular genes. This means that each type of cell makes use of a particular subset of genes to make the particular proteins that type of cell needs. This process of cell differentiation enables cells to acquire the distinctive appearance and functions of neurons characteristic of their particular regions (FIGURE 4.3C). Once they take on the characteristics of neurons, they begin making synaptic connections with one another, in the process of synaptogenesis (FIGURE 4.3D). The particular fate of a differentiating cell depends on where in the brain the cell happens to be and what the cell's neighbors are doing. Cells in the developing brain are constantly sending chemical signals to one another, each shaping the development of the other. This is the hallmark of vertebrate development: cells sort themselves out
FIGURE 4.3 The Six Stages of Neural Development
Cells of the neural tube divide to provide progeny cells.
(B) The cells produced migrate to their appropriate regions.
Each cell differentiates, expressing (C) a particular subset of genes, to become a particular type of neuron or glial cell.
Central canal Neurogenesis (D) Neurons extend their axons and dendrites and form many synapses with one another.
Cell migration (E) Many neurons normally die early in development.
Cell differentiation (F) Many of the synapses initially formed...
...while other, laterappearing synapses form (shown in blue).
via cell-cell interactions, taking on fates that are appropriate in the context of what Wnaetisgohnb/Borreiendglocveells are doing. When the negotiations are all over, if things go properly, a The Mind's Machine FnouenwdaptieonrssoofnBirsaifnoarnmdeBdehwaviitohr 4aell the types of cells in the brain that they need to live. This system of cell-cell interactions determining how brain cells develop has an MimMp4oe_r0t4a.n03t co0n2s/e2q4/u2e0nce: If cells that have not yet differentiated extensively can be obtained and placed in a particular brain region, they can differentiate in an appropriate way and become properly integrated. Such undifferentiated cells, called stem cells, are present throughout embryonic tissues, so they can be gathered from umbilical cord blood, miscarried embryos, or unused embryos produced during in vitro fertilization. It may even be possible someday to take cells from adult tissue and, by treating them
cell-cell interaction The general process during development in which one cell affects the differentiation of other, usually neighboring, cells. stem cell A cell that is undifferentiated and therefore can take on the fate of any cell that a donor organism can produce.
From E. Bruel-Jungerman, et al., 2006. J. Neurosci. 26: 5888. © 2006 Society for Neuroscience
adult neurogenesis The creation of new neurons in the brain of an adult. cell death Also called apoptosis. The developmental process during which "surplus" cells die.
BrdU (bromodeoxyuridine) is a label that is selectively incorporated into the DNA of cells that are about to divide.
NeuN selectively labels neurons (green cells), in order to distinguish them from other nearby cells, such as glial cells.
20 µm Merging the two images makes it clear that some of the newly born cells are, in fact, neurons.
FIGURE 4.4 Neurogenesis in the Dentate Gyrus
wWaitthsonv/aBriroeeudslofvaectors in a dish, transform them into stem cells (Dulak et al., 2015). It The Mind's Machine iFsouhnodpateiodnsthofaBtrpailnaacnind gBeshtaevmior c4ee lls in areas of brain degeneration, such as loss of myelin in multiple sclerosis (see Chapter 2) or loss of dopaminergic neurons in Parkinson's dMiMse4aes_e04(.s0e4e C0h2/a2p4t/e2r05), might reverse such degeneration as the implanted cells differentiate to fill in for the missing components (Y. K. Wang et al., 2018). In the adult brain, newly born neurons aid learning At birth, mammals have already produced most of the neurons they will ever have. The postnatal increase of human brain weight (see Figure 4.2) is due primarily to growth in the size of neurons, branching of dendrites, elaboration of synapses, increase in myelin, and addition of glial cells. But research has shown that we are also capable of adult neurogenesis, the generation of new neurons in adulthood, especially in the dentate gyrus of the hippocampal formation (FIGURE 4.4) (Anacker et al., 2018; Boldrini et al., 2018). By one estimate, 700 new neurons are produced every day in the adult human hippocampus (Spalding et al., 2013). Indeed, although the new neurons acquired in adulthood represent just a tiny minority of the total, there's reason to think they matter (Snyder, 2019). In experimental animals, the birth and/or survival of new neurons is enhanced by factors like exercise, environmental enrichment, and training (Opendak and Gould, 2015). Neurogenesis appears to enhance various forms of hippocampus-dependent learning, such as spatial memory and fear conditioning, in some (but not all) studies (Kee et al., 2007). Mice with a genetic manipulation that turns off neurogenesis in the brains of adults showed a marked impairment in spatial learning with little effect on other behaviors (C. L. Zhang et al., 2008). So by studying this chapter, you may be giving your brain a few more neurons to use on exam day! Physical exercise also boosts neurogenesis in rats--an effect that can be blocked by stressors such as social isolation (Stranahan et al., 2006)--so invest in exercise and a network of friends too. The death of many neurons is a normal part of development As strange as it may seem, cell death is a crucial phase of brain development (FIGURE 4.3E). This developmental stage is not unique to the nervous system. Naturally occurring cell death, also called apoptosis (from the Greek apo, "away from," and ptosis, "act of falling"), is evident as a kind of sculpting process in the emergence of other tissues in both animals and plants.
The pattern of neuronal cell death in spinal motor neurons of chicks...
(B) 200,000 Watson/Breedlove The1M75in,0d0'0s Machine Foundations of Brain and Behavior 4e
...resembles that of humans. Many other neuronal populations show a similar pattern of apoptosis.
(BF)IGURE 4.5 Many Neurons Die during Normal Early
De2v00e,l0o0p0ment (Part A after V. Hamburger, 1...9r7e5se.mJ.bCleos mthpat. of Neurol. 160: 535; B after N. G. Forger andhSu.mMa.nBs.rMeeadnyloovteh,er
The number of neurons that die during early development is quite large. In some regions of the brain and spinal cord, most of the young nerve cells die during prenatal development. In 1958, Viktor Hamburger (1900-2001) first described naturally occurring neuronal cell death in chicks, in which nearly half the originally produced spinal motor neurons die before the chick hatches. A similar loss of spinal motor neurons was later reported in developing humans (FIGURE 4.5). These cells are not dying because of a defect. Rather, these cells die as a consequence of complex interactions with surrounding cells, so they are actively "committing suicide." Your chromosomes carry death genes--genes that are expressed only when a cell undergoes apoptosis (Yamaguchi and Miura, 2015). Genetically interfering with death genes in fetal mice causes them to grow brains that are too large to fit in the skull (Depaepe et al., 2005), so we can see how vital it is that some cells die. Neurons compete for connections to target structures (other nerve cells or end organs, such as muscle). Cells that make adequate synapses remain; those without a place to form synaptic connections die. Apparently the cells compete not just for synaptic sites, but for a chemical that the target structure makes and releases. Neurons that receive enough of the chemical survive; those that do not, die. Such target-derived chemicals are called neurotrophic factors (or simply trophic factors) because they act as if they "feed" the neurons to help them survive (in Greek, trophe means "nourishment") (FIGURE 4.6). That same competition for neurotrophic factors probably also controls the next phase of development, when an enormous proliferation of synapses is followed by a careful pruning, as we'll see next.
neurotrophic factor Also called simply trophic factor. A target-derived chemical that acts as if it "feeds" certain neurons to help them survive.
FIGURE 4.6 A Model for the Action of Neurotrophic Factors
1 Different neurotrophic factors are produced by different target cell groups. Target cells
2 Innervating neurons take up particular neurotrophic factors and transport them to their cell bodies.
3 Upon reaching the cell body, neurotrophic factors regulate the expression of various genes, affecting the development of the neuron.
4 Early in development, neurons that manage to gather suf cient amounts of the appropriate neurotrophic factor survive. Neurons that gather insuf cient trophic factor die. 5 Because the amount of neurotrophic factor matches the number of target cells, this process results in a rough matching of the size of the target and the number of innervating neurons. 6 Later in development, axonal processes also compete for neurotrophic factors. Active synapses compete more successfully than inactive synapses. 7 Because experience can modulate synaptic activity, different experiences can result in the maintenance of different patterns of synaptic connectivity.
Watson/Breedlove The Mind's Machine Foundations of Brain and Behavior 4e 1. What six stages of cellular processes take place in the developing brain? MM2.4eW_0h4a.0t6is c0e2l/l 2d4i/ff2e0rentiation, and what guides this process in each cell in the developing brain? 3. What two classes of brain structures undergo loss during development? 4. What are neurotrophic factors, and what role do they play in brain development?
Development of the Brain 129 4.2An Explosion of Synapse Formation Is Followed by Synapse Rearrangement
Now we describe the lifelong process by which synapses are lost and gained in the brain. Learning this material should allow you to: 4.2.1 Describe the process of synapse rearrangement, and offer evidence that a net loss of synapses may be adaptive. 4.2.2 Describe studies showing that visual experience early in life is required to develop normal vision. Before birth and after, neurons in the human cortex grow ever longer and more elaborate dendrites, each jammed with synapses. As we noted earlier, this massive increase in dendrites and synapses is responsible for most of the increase in brain size after birth (FIGURE 4.7). But just as not all the neurons produced by a developing individual are kept into adulthood, some of the synapses formed early in development are later retracted. Some original synapses are lost, and many, many new synapses are formed (FIGURE 4.3F). This synapse rearrangement, or synaptic remodeling, typically takes place after the period of cell death. For example, as we learned already, about half of the spinal motor neurons that form die later (see Figure 4.5). By the end of the cell death period, each surviving motor neuron innervates many muscle fibers, and every muscle fiber is innervated by several motor neurons. But later the surviving motor neurons retract many of their axon collaterals, until each muscle fiber comes to be innervated by only one motor neuron. Again, which synaptic connections are retained, and which new connections are formed, is thought to depend on competition for trophic factors during development (see Figure 4.6) and/or competition between Hebbian synapses (see Figure 13.22).
synapse rearrangement Also called synaptic remodeling. The loss of some synapses and the development of others.
These representations of cerebral cortex show the extent of neural connections and neuronal differentiation at birth... (A) I
In these gures, only a few of the millions of neurons present are illustrated so we can appreciate how much their dendrites are expanding. I II
From J. L. Conel, 1939. The postnatal development of the human cerebral cortex: Vol. 1. The cortex of the newborn; 1947, Vol. 3. The cortex of the three-month infant; 1959, Vol. 6. The cortex of the twenty-four-month infant. Harvard University Press. Cambridge, MA
IV V The mature cerebral cortex contains six layers. VI
FIGURE 4.7 Cerebral Cortex Tissue in the Early Development of Humans
FIGURE 4.8 The Postnatal Development of Synapses in
Human Cortex (After P. R. Huttenlocher and A. S. Dabholkar,
1997. J. Comp. Neurol. 387: 167.) Watson/Breedlove
Similar events have been documented in several neural regions, including the cerebellum, the brainstem, the visual cortex, and the autonomic nervous system (Lichtman and Purves, 1980). In human cerebral cortex there is a net loss of synapses from late childhood until midadolescence (FIGURE 4.8). This synaptic remodeling is evident in thinning of the cortical gray matter as pruning of dendrites and axon terminals progresses. The thinning process continues in a caudal-rostral (posterior-anterior) direction during maturation (FIGURE 4.9), so prefrontal cortex matures last (Gogtay et al., 2004). Since prefrontal cortex is important for inhibiting behavior (see Chapter 14), this delayed brain maturation may contribute to teenagers' impulsivity and relative lack of control (Paus et al., 2008). What determines which synapses are kept and which are lost? Although we don't know all the factors, one important influence is neural activity. One theory is that active synapses take up some neurotrophic factor that maintains the synapse, while inactive synapses get too little trophic factor to remain stable (see Figure 4.6). Intellectual stimulation probably contributes, as suggested by the fact that teenagers with the highest IQ show an especially prolonged period of cortical thinning (P. Shaw et al., 2006). Another stage of brain development, the formation of myelin sheaths for axons, is discussed in A STEP FURTHER 4.1, on the website. many synapses can impair intellectual development
inMteMll4eec_t0u4a.0l8dis0a9b/i0l2it/y20 A disability characterized by significant limitations in intellectual functioning and adaptive behavior.
One syndrome indicates that the loss of synapses actually helps the brain function better. The most frequent inherited cause of intellectual disability, a significant limitation in intellectual functioning and adaptive behavior, is fragile X syndrome
fragile X syndrome A condition that is a frequent cause of inherited intellectual disability and is produced by a fragile site on the X chromosome that seems prone to breaking because the DNA there is unstable.
The layer of gray matter on the surface of the cortex gets thinner throughout development, as synapses are retracted. Purple and blue depict regions with little change in cortical thickness.
Yellow and red depict areas that are changing rapidly at this age.
Note that the prefrontal cortex, usually thought to be important in inhibiting behavior, does not nish maturation until adolescence.
From N. Gogtay et al., 2004. Proc. Natl. Acad. Sci. USA 101: 8174. © National Academy of Sciences, U.S.A.
FIGURE 4.9 Synapse Rearrangement in the Developing Human Brain
Courtesy of Kelley Devine and Patrick Devine
(FIGURE 4.10). Researchers have found that some people are born with an X chromosome that is prone to breaking because the DNA at one site is unstable (Lyons et al., 2015). A person with this condition has a modified facial appearance, including elongation of the face, large prominent ears, and a prominent chin. A wide range of cognitive effects--from mild to severe impairment--are associated with the syndrome. Cortical neurons from the brains of people with fragile X syndrome, as well as mice genetically engineered to have this syndrome, possess an excess of small, immature dendritic spines (Bagni and Greenough, 2005). These findings suggest that the syndrome affects mental development by blocking the normal elimination of synapses after birth (see Figure 7.9). We'll run into lifelong synaptic rearrangement repeatedly in this book. In Chapter 5 we'll see that regions of cerebral cortex that process touch information undergo synapse rearrangement throughout life, and in Chapter 13 we'll find that learning and memory happen through the strengthening and weakening of existing synapses or through synapse rearrangement. Next we'll consider another example of synaptic rearrangement, in the visual system, where experience is crucial for proper development.
FIGURE 4.10 Too Many Synapses? A man with fragile X syndrome.
Some people do not see forms clearly with one of their eyes, even though the
eye is intact and a sharp image is focused on the retina. Such impairments of
vision are known as amblyopia (from the Greek amblys, "dull," and ops, "eye"). Some
people with this disorder have an eye that is turned inward (are cross-eyed) or outward. Children born with such a misalignment see a double image rather than a single fused
one eye that is not caused by optical or retinal impairments.
image. By the time an untreated person reaches the age of 7 or 8, pattern vision in the deviated eye is almost completely suppressed. If the eyes are realigned during childhood, the person learns to fuse the two images and has good depth perception. But if realignment is done in adulthood, it's too late to restore acute vision to the turned eye. Much of what we know about the causes of amblyopia comes from visual deprivation experiments with lab animals, in which the eyelids are reversibly sutured shut or
binocular deprivation Depriving both eyes of form vision, as by sealing the eyelids. sensitive period The period during development in which an organism can be permanently altered by a particular experience or treatment.
the animal is fitted with frosted contact lenses, thereby preventing focused images on
the retina. These experiments have revealed startling changes related to disuse of the
visual system in early life. Binocular deprivation, depriving animals of sight in both
eyes, produces structural changes in visual cortical neurons: a loss of dendritic
spines and a reduction in synapses. If such deprivation is maintained for several weeks during development, when the animal's eyes are opened, it will be
Because experience determines which synapses will be maintained, this is a crucial stage of neural plasticity.
the messages, and the animal is unable to detect visual stimuli. If the depri-
early visual experience is crucial for the Brain
the sensitive period, the manipulations FIGURE 4.11 Brain Development in the Visual Cortex of Cats (After B. G. Cragg,
Watson/Breedlove The Mind's Machine Foundations of Brain and Behavior 4e
monocular deprivation Depriving one eye of light. ocular dominance histogram A graph that portrays the strength of response of a brain neuron to stimuli presented to either the left eye or the right eye.
Depriving only one eye of light during the developmental sensitive period-- monocular deprivation--produces profound structural and functional changes in the thalamus and visual cortex and permanently impairs vision in the deprived eye. The effect of visual deprivation can be illustrated graphically by an ocular dominance histogram, which portrays the strength of response of a brain neuron to stimuli presented to either the left or the right eye. Normally, most cortical neurons (except those in layer IV) are excited equally by light presented to either eye (FIGURE 4.12A). Keeping one eye closed or covered in development results in a striking shift from the normal graph; most cortical neurons now respond only to input from the nondeprived eye
FIGURE 4.12 Ocular Dominance Histograms (A and C after D. H. Hubel and T. N. Wiesel, 1965. J. Neurophysiol. 28: 1041; B after T. N. Wiesel and D. H. Hubel, 1965. J. Neurophysiol. 28: 1029.)
The numbers along the x-axis represent a gradation in response: Cells that respond only to stimulation of the opposite eye are class 1 cells. Cells that respond mainly to stimulation of the opposite eye are class 2. Cells that respond equally to either eye are class 4. Cell that respond only to stimulation of the eye on the same side are class 7, and so on.
Most cortical cells become binocular as the two eyes are stimulated by experience.
Monocular deprivation in development can lead to blindness in that eye. Similar deprivation in adulthood has virually no effect.
If one eye is deviated, each cortical cell will respond to only one eye or the other, resulting in poor depth perception.
Left eye open: Neighboring retinal cells tend to re synchronously, and thus tend to drive the postsynaptic neuron to re. Right eye covered: With no visual stimulation, cells tend to re at random, and rarely cause the postsynaptic neuron to re.
Strengthening of synapses that successfully drive postsynaptic cell Loss of ineffective inputs Visual cortical cell
Hebbian synapses can account for changes after monocular deprivation. By adulthood, the cortical cell responds only to signals from the open eye.
(FIGURE 4.12B). In cats the critical period for this effect is the first 4 months of life. In rhesus monkeys the sensitive period extends to age 6 months. After these ages, visual deprivation has little effect. During early development, synapses are rearranged in the visual cortex, and axons representing input from each eye "compete" for synaptic places. Active, effective synapses predominate over inactive synapses. Thus, if one eye is "silenced," synapses carrying information from that eye are retracted while synapses driven by the other eye are maintained. Donald O. Hebb (1949) proposed that effective synapses (those that successfully drive the postsynaptic cell) might grow stronger at the expense of ineffective synapses. Thus, synapses that grow stronger or weaker depending on their effectiveness in driving their target cell are known as Hebbian synapses (FIGURE 4.12D). In Chapter 13 we will learn about a particular neurotransmitter receptor, the NMDA receptor, that causes synapses to act like Hebbian synapses, and likely plays a role in learning and memory (see Figure 13.22). Researchers offer a similar explanation for amblyopia produced by misalignment of the eyes. Hubel and Wiesel (1965) produced an animal replica of this human condition by surgically causing the eyes to diverge in kittens. The ocular dominance histogram of these animals reveals that the normal binocular sensitivity of visual cortical cells is greatly reduced (FIGURE 4.12C). A much larger proportion of visual cortical cells is excited by stimulation of either the right or the left eye in these animals than in control animals. The reason for this effect is that after surgery, visual stimuli falling on the misaligned eyes no longer provide simultaneous, convergent input to the cells of the visual cortex. Neurotrophic factors may be playing a role in experience-driven synapse rearrangement. For example, if the postsynaptic cells are making a limited supply of a neurotrophic factor, and if active synapses take up more of the factor than inactive synapses do, then perhaps the inactive axons retract for lack of neurotrophic factor. Brain-derived neurotrophic factor (BDNF) has been implicated as a neurotrophic factor being competed for in the mammalian visual cortex (Sansevero et al., 2019). So perhaps ineffective synapses wither for lack of neurotrophic support. In A STEP FURTHER 4.2 on the website, you can learn how mouse whiskers compete for synapses in the cortex. Early exposure to visual patterns helps fine-tune connections in the visual system Human disorders have also proven that early experience is crucial for vision. Babies born with cataracts (cloudy lenses) in industrialized countries usually have them removed a few months after birth and will have good vision. But if such a child grows up with the cataracts in place, removing them in adulthood is much less effective; the adults acquire the use of vision slowly (Ostrovsky et al., 2009) and to only a limited extent (Bower, 2003). Early visual experience is known to be especially crucial for learning to perceive faces, because infants with cataracts that occlude vision for just the first 6 months of life are impaired at recognizing faces even 9 years later (Le Grand et al., 2001). These experience-dependent effects are probably mediated by synapse rearrangement within the visual cortex (Ruthazer et al., 2003) like that seen in kittens. Why does Michael May, whom we met at the start of the chapter, have such poor vision despite the clear images entering his eye? Had the accident happened to him as an adult, the surgery to let light back into his eye would have restored normal vision. But, like a kitten growing up with opaque contact lenses, Michael was deprived of form vision, beginning while he was a child and lasting for 40 years. So, synaptic connections within his developing visual cortex were not strengthened by the patterns of light moving across the retina, and in the absence of patterned stimulation, synapses between the eye and the brain languished and disappeared. In one sense, Michael was lucky that his blindness came as late as it did. He had normal form vision for the first 3½ years of his life, and that stimulation may have been sufficient to maintain some synapses that would otherwise have been lost. These
Hebbian synapse A synapse that is strengthened when it successfully drives the postsynaptic cell. Learning to See Michael May finds it particularly difficult to recognize faces by sight alone.
Controls have no dif culty distinguishing objects by sight alone. Tested shortly after his surgery, Mike May recognized objects less than 30% of the time. Ten years later, Mike showed no signi cant improvement in object recognition.
Despite having the damage to his eye surgically corrected as an adult, Michael May was rather poor at distinguishing between basic objects, like spheres versus cubes. When retested 10 years later, there was no signi cant improvement in his ability to distinguish objects by sight alone.
residual synapses are probably what allow him to make any sense whatsoever of his vision. Yet, despite more than a decade of visual experience as an adult, Michael still has problems distinguishing three-dimensional objects or faces (FIGURE 4.13) (Huber et al., 2015). Other people who gain vision for the first time as adults have similar dWifaftiscounl/tiBerseerdecloovgenizing objects and faces (Gregory and Wallace, 1963; Sikl et al., 2013). The Mind's Machine Foundations of Brain and Behavior 4e MM1.4We_h04a.t1i3s th0e2/e2v4id/e20nce that early visual experience is important for being able to see? 2. What's an ocular dominance histogram, and what manipulation(s) can alter it in cats? 3. What is a Hebbian synapse, and how might such synapses affect development of the visual system?
4.3Experience Can Affect Brain Development by Altering Gene Expression
In this section we discuss how experience can affect the way genes work. Learning this material should allow you to: 4.3.1 Describe how the environment can regulate gene expression and how experience and genes interact to affect behavior. 4.3.2 Define epigenetic changes, and explain how they might play a role in the interaction of genes and the environment. 4.3.3 Describe the mechanism by which rodent dams can alter their offspring's lifelong stress response. Many factors shape the form, arrangements, and connections of the developing brain. One influence is genes, which direct the production of every protein the cell can make. An individual who has inherited an altered gene will make an altered protein, which will affect every cell that uses that protein. Thus, every neuronal structure, and therefore every behavior, can be altered by changes in the relevant gene(s). It is useful to think of genes as intrinsic factors--that is, factors that originate within the developing cell itself. All other influences we can consider extrinsic--originating outside of the developing cell.
Genotype is fixed at birth, but phenotype changes throughout life Two terms help illustrate how these intrinsic and extrinsic factors interact. The sum of all the intrinsic, genetic information that an individual has is its genotype. The sum of all the anatomical, physiological and behavioral characteristics that make up an individual is its phenotype. Your genotype was determined at the moment of fertilization and remains the same throughout your life. But your phenotype changes constantly, as you grow up and grow old and even, in a tiny way, as you take each breath. In other words, phenotype is determined by the interaction of genotype and extrinsic factors, including experience. Thus, as we'll see, individuals who have identical genotypes do not have identical phenotypes, because they have not received identical extrinsic influences. And since their nervous system phenotypes are somewhat different, they do not behave exactly the same. Several hundred different genetic disorders affect the metabolism of proteins, carbohydrates, or lipids, having a profound impact on the developing brain. Characteristically, the genetic defect is the absence of a particular enzyme that controls a critical biochemical step in the synthesis or breakdown of a vital body product. An example is phenylketonuria (PKU), a heritable disorder of protein metabolism that at one time resulted in many people with intellectual disability. About one out of 100 persons is a carrier; one in 10,000 births produces an affected victim. The basic defect is the absence of an enzyme necessary to metabolize phenylalanine, an amino acid that is present in many foods. As a result, the brain is damaged by an enormous buildup of phenylalanine, which becomes toxic. The discovery of PKU marked the first time that an inherited error of metabolism was associated with intellectual disability. These days, the level of phenylalanine in the blood is measured in children a few days after birth. Early detection is important because brain impairment can be prevented simply by reducing phenylalanine in the diet. Such dietary control of PKU is critical during the early years of life (L. Bernstein et al., 2017). Note this important example of the interaction of genes and the environment in PKU: the dysfunctional gene causes intellectual disability only in the presence of phenylalanine. Reducing phenylalanine consumption reduces or prevents this effect of the gene. PKU illustrates one reason why, despite the importance of genes for nervous system development, understanding the genotype alone could never enable an understanding of the developing brain. Knowing that a baby is born with PKU doesn't tell you anything about how that child's brain will develop unless you also know something about the child's diet. Another reason why genes alone cannot tell the whole story is that experience can affect the activity of genes, as we discuss next. Experience regulates gene expression in the developing and mature brain Genetically identical animals, called clones, used to be known mainly in science fiction and horror films. But life imitates art. In pigs, genetically identical clones show as much variation in behavior and temperament as do normal siblings (G. S. Archer et al., 2003), and genetically identical mice raised in different laboratories behave very differently on a variety of tests (Finch and Kirkwood, 2000). If genes are so important to the developing nervous system, how can genetically identical individuals differ in their behavior? Recall that although nearly all of the cells in your body have a complete copy of your genotype, each cell uses only a small subset of those genes at any one time. We mentioned earlier that when a cell uses a particular gene to make a particular protein, we say the cell has expressed that gene. Epigenetics is the study of factors that affect gene expression without making any changes in the nucleotide sequence of the genes. The same protein is produced, but the amount of protein can vary considerably, which leads to variation in brain development. We'll consider two factors that may affect gene expression next.
genotype All the genetic information that one specific individual has inherited. phenotype The sum of an individual's physical characteristics at one particular time. phenylketonuria An inherited disorder in which the absence of an enzyme leads to a toxic buildup of phenylalanine metabolites, causing intellectual disability. clones Asexually produced organisms that are genetically identical. epigenetics The study of factors that affect gene expression without making any changes in the nucleotide sequence of the genes themselves. Be Careful What You Eat Millie Lonergan, who has phenylketonuria, eats fruit and protein-free rice and pasta (without cheese) for a diet low in phenylalanine.
Hypothesis The behavior of genetically identical male mice can be affected by the prenatal environment and/or the mothering they receive after birth.
Experiment Take genetically identical mouse embryos of the Black6 strain, and implant them into the womb of a foster mother of either their own strain or another strain (the albino Balb strain). After birth, transfer half the males to be raised by either a Black6 female or a Balb female. When the males grow up, measure their behavior on tests in which Black6 and Balb mice normally differ.
At birth, cross-foster to a mother of either the Black6 or albino strain.
Transfer Black6 embryos to female of same or different strain for prenatal development.
Result Males of the Black6 strain carried and raised by mothers from the albino strain show significant differences in several behaviors (Francis et al., 2003), including maze running and measures of anxiety (Figure 4.14). Conclusion Since the various males are genetically identical to one another, their different behaviors must be due to the effect of different prenatal environments and postnatal experiences, such as the mothering they received, on how those genes are expressed.
Black6 males carried and raised by albino mothers behaved like albino males in many ways: they explored less, acted more anxious, and were slower to solve mazes than normal Black6 males.
Black6 males carried by albino mice, but raised by Black6 mice, acted like albino males in some ways: they were more anxious and slower at maze solving than normal Black6 males, but they explored like normal Black6 males.
Black6 males carried by Black6 mice, but raised by albino mothers, behaved like normal Black6 males in most ways, but they did act slightly more anxious than normal Black6 males, making them more like albino males.
As expected, Black6 males carried by Black6 females, and cross-fostered to Black6 mothers, acted like normal Black6 males.
FIGURE 4.14 Epigenetic Effects on Mouse Behavior (After D. D. Francis et al., 2003. Nat. Neurosci. 6: 445.)
methylation A chemical modification of DNA that does not affect the nucleotide sequence of a gene but makes that gene less likely to be expressed.
Gene expression in the brain can be affected by mothering One particular influence of mothering on gene expression has been well documented. Methylation is a chemical modification of DNA that does not affect the nucleotide sequence of a gene but makes that gene less likely to be expressed. Rodent pups provided with inattentive mothers, or subjected to interruptions in maternal care, secrete more glucocorticoids in response to stress as adults (T. Y. Zhang and Meaney, 2010). Poor maternal care produces this heightened stress hormone response by inducing methylation of the glucocorticoid receptor gene in the brain, making the pups hyperresponsive to stress for the rest of their lives (FIGURE 4.15). A similar mechanism may apply to humans, because this same gene is also more likely to be methylated in the postmortem brains of suicide victims than of controls, but only in those victims who were subjected to childhood abuse. Suicide victims who did not suffer childhood abuse were no more likely to have the gene methylated than were controls (McGowan et al., 2009). These results suggest that methylation of the gene in abused children may make them hyperresponsive to stress as adults--a condition that may lead them to take their own lives. This is a powerful demonstration
(A) Low maternal licking (A) and grooming
(B) High maternal licking (B) and grooming
Regulatory Stress hormone region receptor gene Hormone receptor expression in the brain High stress hormone levels High anxiety Low licking and grooming
Regulatory Stress hormone region receptor gene Hormone receptor expression in the brain Low stress hormone levels Low anxiety High licking and grooming
Attentive rodent mothers prevent methylation of the stress hormone receptor gene in their pups, so their daughters grow up to be attentive mothers themselves. In this way, maternal care can have epigenetic effects that can be transmitted across generations.
FIGURE 4.15 Early Experience Imprints Genes to Affect the Stress Response in Adulthood (After D. A. Hackman et al., 2010. Nat. Rev. Neurosci. 11: 651.)
of epigenetic influences on behavior. Other developmental disorders are also influenced by both genes and the environment, as we discuss in A STEP FURTHER 4.3, on the website. Taken together, these studies lead us to the conclusion that the incredible intelligence of the adult human is due not only to the inheritance of genes provided us by natural selection, but also to the effect of the environment and experience that deter- Watson/Breedlove mThienMesinwd'hseMreacahninde when those genes are expressed in the brain, especially in developmFouenndta.tiTonhsuosf,Btrhaien atnredmBeehnavdiooru4se, fetal-like development of the human brain after birth (see Figure 4.2) is molded by experience and social guidance. We wish we could tell MM4e_04.15 06/30/20 you that once your brain has been sharpened by experience (including what you gain by reading this book), you will remain brilliant forever. Sadly, development continues relentlessly toward old age. Just as our faces and bodies weaken and fade, the brain also declines, the depressing topic that concludes this chapter.
1. Compare changes in genotype and phenotype in an individual during development and aging. 2. How does PKU illustrate an interaction between genes and the environment? 3. Describe two demonstrations of epigenetic effects on development.
4.4The Brain Continues to Change as We Grow Older In the final part of this chapter, we consider the aging brain. Learning this material should allow you to: 4.4.1 Describe the current model of processes underlying the degeneration seen in Alzheimer's disease. 4.4.2 Critique the amyloid hypothesis of Alzheimer's. 4.4.3 Discuss how brain imaging may help us understand the mechanism(s) of Alzheimer's. The passage of time brings us an accumulation of joys and sorrows--perhaps riches and fame--and a progressive decline in many of our abilities. Although slower responses seem inevitable with aging, many of our cognitive abilities show little change during the adult years, until we reach an advanced age. What happens to brain structure from adolescence to the day when we all become a little forgetful and walk more hesitantly? Memory impairment correlates with hippocampal shrinkage during aging In a study of healthy and cognitively normal people age 55-87, investigators asked whether mild impairment in memory is specifically related to reduction in size of the hippocampal formation or is better explained by generalized shrinkage of brain tissue. Volunteers took a series of memory tests, and their brains were measured from MRI images (FIGURE 4.16). When effects of sex, age, IQ, and overall brain atrophy were eliminated statistically, hippocampal formation volume was the only brain measure that correlated significantly with memory. PET scans of elderly people reveal that cerebral metabolism normally remains almost constant as we age. This stability is in marked contrast to the dramatic decline of brain activity in Alzheimer's disease, which we will consider next. Alzheimer's disease is associated with a decline in cerebral metabolism The population of elderly people in the United States is increasing dramatically. Most people reaching an advanced age lead happy, productive lives, although at a slower pace than they did in their earlier years. In a growing number of elderly people, MRI images illustrate the hippocampal formation (red), the supratemporal gyrus (orange), and the space between brain and skull (yellow-green). Only size of the hippocampal formation is correlated with memory decline.
From J. Golomb et al., 1994. J. Neurol. Neurosurg. Psychiatry 57: 590. MRI courtesy of James Golumb
FIGURE 4.16 Hippocampal Shrinkage Correlates with Memory Decline in Aging
however, age has brought a particular agony: the disorder called Alzheimer's disease, named after Alois Alzheimer (1864-1915), the neurologist who first described a type of dementia (drastic failure of cognitive ability, including memory failure and loss of orientation). Nearly 6 million Americans suffer from Alzheimer's disease, and the progressive aging of our population means that these ranks will continue to swell (Alzheimer's Association, 2019). This disorder is found worldwide with almost no geographic differences. The frequency of Alzheimer's increases with aging up to age 85-90, but people who reach that age without symptoms become increasingly less likely ever to develop them (Breitner et al., 1999; Y. Zhao et al., 2018). This last finding indicates that Alzheimer's is in fact a disease, and not simply the result of wear and tear in the brain. The fact that remaining physically and mentally active reduces the risk of developing Alzheimer's disease (Gallagher et al., 2019) also refutes the notion that brains simply "wear out" with age. Extensive use of the brain makes Alzheimer's less likely. Alzheimer's disease begins as a loss of memory of recent events. Eventually this memory impairment becomes all-encompassing, so extensive that people with Alzheimer's cannot maintain any form of conversation, because both context and prior information are rapidly lost. They cannot answer simple questions such as, What year is it? Who is the president of the United States? or Where are you now? Cognitive decline is progressive and relentless. In time, people with Alzheimer's become disoriented and easily lose themselves even in familiar surroundings. Observations of the brains of people with Alzheimer's reveal striking cortical atrophy (shrinkage), especially in the frontal, temporal, and parietal areas. PET scans show marked reduction of metabolism in posterior parietal cortex and some portions of the temporal lobe (see Figure 1.18E) (Teipel et al., 2016). The brains of individuals with Alzheimer's also reveal progressive changes at the cellular level (FIGURE 4.17): · Strange patches termed amyloid plaques appear in cortex, the hippocampus, and associated limbic system sites. The plaques are formed by the buildup of a substance called beta-amyloid (Selkoe and Hardy, 2016), which is how amyloid plaques got their name.
Alzheimer's disease A form of dementia that may appear in middle age but is more frequent among the aged. dementia Drastic failure of cognitive ability, including memory failure and disorientation. amyloid plaque Also called senile plaque. A small area of the brain that has abnormal cellular and chemical patterns. Amyloid plaques correlate with dementia. beta-amyloid A protein that accumulates in amyloid plaques in Alzheimer's disease.
The basal forebrain nuclei project their axons, which use acetylcholine as a neurotransmitter, widely across the brain. These cells seem to disappear in Alzheimer's patients.
...and amyloid plaques are visible in this section of cerebral cortex from a patient with Alzheimer's.
FIGURE 4.17 People with Alzheimer's Show Structural Changes in the Brain
140CHAPTER4 neurofibrillary tangle An abnormal whorl of neurofilaments within nerve cells that is seen in Alzheimer's disease.
· Some cells show abnormalities called neurofibrillary tangles, which are abnormal whorls of neurofilaments that form a tangled array inside the cell. The number of neurofibrillary tangles is directly related to the magnitude of cognitive impairment, and they are probably a secondary response to amyloid plaques. · People with Alzheimer's gradually lose many neurons in the basal forebrain, which make the transmitter acetylcholine (ACh). Drugs that boost ACh signaling may reduce some of the symptoms of Alzheimer's for a time. One hypothesis about how these processes are related to each other is offered in A STEP FURTHER 4.4, on the website. Perhaps measuring beta-amyloid will help future Alzheimer's research, as Signs & Symptoms discusses next.
From M. Maruyama et al., 2013. Neuron 79: 1094
SIGNS & SYMPTOMS Imaging Alzheimer's Plaques At present, the only surefire diagnosis for Alzheimer's is postmortem examination of the brain revealing amyloid plaques and neurofibrillary tangles. But one innovative approach is to inject the dye Pittsburgh Blue (PiB), which has an affinity for beta-amyloid (Sheikh-Bahaei et al., 2018). Then a PET scan determines how much of the dye accumulates in the brain. The brain of virtually every person diagnosed with Alzheimer's accumulates the dye, as do the brains of many elderly people showing mild cognitive impairment (FIGURE 4.18). A meta-analysis of findings from thousands of participants confirmed that levels of amyloid, as revealed by PiB imaging, indeed correlated with who would develop Alzheimer's (Ossenkoppele et al., 2015). One important implication of this finding is that now it will be easier to track the effectiveness of various therapies for Alzheimer's. One treatment strategy is to develop drugs that interfere with enzymes that favor beta-amyloid production (O. Singer et al., 2005; Yu et al., 2015). However, there is increasing skepticism about whether beta-amyloid actually causes the symptoms of Alzheimer's, or whether the accumulating amyloid is the result of something the brain is doing to avoid the symptoms of Alzheimer's (Makin, 2018). In that case, interfering with amyloid production would not help, and might even exacerbate the disease. Supporting that gloomy idea, several manipulations in mice that successfully interfered with amyloid accumulation provided no behavioral benefit. In the meantime, and in keeping with the repeated theme of this chapter--that genes and experience interact--there is good evidence that physical activity (Ngandu et al., 2015), mental activity (Gates and Sachdev, 2014), and adequate sleep (Gelber et al., 2015) can postpone the appearance of Alzheimer's disease. So unless you want to pin your hopes on medical miracles in the future, the best way to avoid suffering from Alzheimer's is to remain physically and mentally active. Perhaps you should consider a career in neuroscience research...
By injecting radiolabeled markers, scientists can image Tau tangles, which are concentrated in the hippocampus (indicated by arrowheads) of a person with Alzheimer's disease (AD) compared with a healthy control (HC). Similarly, Pittsburgh Blue can reveal -amyloid, which is abundant throughout the brain of a person with AD.
FIGURE 4.18 Imaging Tau Tangles and Amyloid Plaques in the Brain
Watson/Breedlove The Mind's Machine Foundations of Brain and Behavior 4e
1. What is Alzheimer's disease, and how is it diagnosed? 2. Why is beta-amyloid a suspected cause of Alzheimer's? 3. Although genes clearly influence the risk of Alzheimer's, what environmental factors can postpone its onset? Recommended Reading Barresi, M. J. F., and Gilbert, S. F. (2019). Developmental Biology (12th ed.). Sunderland, MA: Oxford University Press/Sinauer. Breedlove, S. M. (2017). Foundations of Neural Development. Sunderland, MA: Oxford University Press/Sinauer. Marcus, G. (2008). The Birth of the Mind: How a Tiny Number of Genes Creates the Complexities of Human Thought. New York, NY: Basic Books.
4 · VISUAL SUMMARY You should be able to relate each summary to the adjacent illustration, including structures and processes. The online version of this Visual Summary includes links to figures, animations, and activities that will help you consolidate the material.
1 The brain develops in six stages: (1) neurogenesis, (2) cell migration, (3) cell differentiation, (4) synaptogenesis, (5) cell death (or apoptosis), and (6) synapse rearrangement. In adulthood, synapse rearrangement continues throughout the brain, and experience guides this process. Some neurogenesis also occurs in adults. Review Figures 4.1-4.5, Animation 4.3, Video 4.4, Activity 4.1 3 Maldevelopment of the brain can occur as a result of mutations or other genetic disorders, including fragile X syndrome, and metabolic disorders such as phenylketonuria (PKU). However, the severity of PKU depends on an environmental factor--the amount of phenylalanine in the diet. Review Figure 4.10 5 While genes play an important role in brain development, the environment and experience, such as mothering, can affect gene expression. That is, genetically identical individuals may behave very differently from one another because of differences in epigenetic influences. Review Figures 4.14 - 4.15
Transfer Black6 embryos to female of same or different strain for prenatal development.
2 The final stage of synapse rearrangement continues to some extent throughout life. Neurotrophic factors seem to regulate which synapses will remain and which will retract. Among the many influences on brain development are genetic information and a multitude of environmental factors such as nutrition and experience. Review Figure 4.6-4.9
4 Experience affects the growth and development of the brain, inducing and modulating the formation of synapses and determining which synapses will survive and which will be eliminated. For example, visually guided synaptic rearrangement is crucial for proper development of the visual system. Review Figures 4.11- 4.13
6 Several genes affect the buildup of beta-amyloid in amyloid plaques and increase the risk of Alzheimer's disease, but there are growing doubts about whether amyloid causes the symptoms. Adequate sleep and mental and physical activity can postpone the onset of the disease. Review Figures 4.16-4.18
The Mind's Machine digital resources include additional videos, flashcards, and other study tools.